DESCRIPTION: MicroRNAs (miRNA) are recently discovered small (-21 nt) RNA species that have important roles in regulation of cellular gene expression. This is to be distinguished from mechanistically related cellular defense mechanisms that are mediated via very similar mechanisms (small interfering RNA, or siRNA), but target exogenous mRNAs, such as those expressed by viruses. The human genome has been predicted to encode as many as 500 to 600 distinct miRNA genes. Targets of miRNA regulation include genes involved in regulation of developmental stages and in cellular differentiation. Different cell types, e.g., neuronal vs. stem cells, express miRNA populations that differ in representation and abundance of individual miRNA species. miRNA activity is manifest as reduced translation from the targeted mRNAs. Herpesviruses are genetically complex viruses that encode as many as 200 genes, of which only about 40 are involved in the fundamental aspects of replicating and packaging the genome for transmission. The remainder are involved in manipulating the cellular and organismal environment to ensure short-term replicative success and virus survival on an evolutionary time scale. Thus, these gene products exercise diverse and profound effects on regulation of host cell metabolism and immune responses. Human cytomegalovirus (HCMV) is an important human pathogen that has one of the genetically most complex herpesvirus genomes, and a correspondingly complex biology. This application is aimed at understanding the relationships between HCMV infection and the expression and function of cellular miRNA genes. We propose two lines of inquiry: Aim 1: Does HCMV infection result in altered expression of cellular miRNA species? Aim 2: What are the biological consequences of virally altered miRNA expression? The significance of the work proposed here rests on it opening a new avenue of research relating to viral use and manipulation of a cellular process that regulates a wide range of outcomes. Potential long-term outcomes of this work include improved diagnostic methods and novel therapeutic strategies. [unreadable] [unreadable] [unreadable]